Clinical Trial of BP1001 (Liposomal Grb2 Antisense Oligonucleotide) in Combination With Dasatinib in Patients With Ph + CML

Study Description

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Brief Summary:

The primary objective of the Phase 1b study is to determine the dose-limiting toxicity (DLT) and maximal tolerated dose (MTD) of BP1001 and Dasatinib (Das) in patients with Philadelphia chromosome positive (Ph+) Chronic Myelogenous Leukemia (CML) in accelerated or blast phase. The primary objective of the Phase IIa study is to assess the efficacy of the combination of BP1001 and Das in patients with Ph+ CML.

Condition or disease	Intervention/treatment	Phase
Chronic Myelogenous Leukemia, Ph1-Positive	Drug: BP1001 (varying dose); Drug: BP1001 (fixed dose); Drug: Dasatinib	Phase 1; Phase 2

Detailed Description:

The Grb2 gene has been mapped to the human chromosome region 17q22-qter, a region that is duplicated in leukemias and solid tumors, which may result in an increased copy number of the Grb2 gene product. As Grb2 is important for the transformation of murine hematopoietic cells, and the proliferation of human leukemia cells that express high levels of oncogenic tyrosine kinases, inhibition of Grb2 may have a significant impact on the natural history of leukemias. The study drug (BP1001) may be able to inhibit the cells from making Grb-2. Researchers hope that without this protein, the leukemia cells will die.

Dasatinib (Das) has been a well established therapeutic regimen in the treatment of Ph+ CML patients who are in accelerated of blast phase. Researchers hope that the combination of BP1001 and Das will provide a benefit to CML patients in accelerated or blast phase, who typically do not respond to the front-line treatment, imatinib.

This is a Phase Ib/IIa, multicenter, study of BP1001 in combination with Das in participants with Ph+ CML who are in accelerated or blast phase.

This trial will utilize a single arm, open label design to assess the safety profile, DLT, MTD, PK, and efficacy of BP1001 in combination with Das.

Phase Ib portion of the study: The Phase Ib study employs an open-label, sequential, dose-escalation design to assess safety, tolerability and toxicity, tumor response and anti-leukemic activity.

A standard "3+3" design will be used in which successive cohorts of patients with CML are being treated with BP1001 at the MTD (or highest tested dose [HTD] if the MTD is not defined) and 1 level below the MTD (or HTD) in combination with a fixed dose of Das to characterize safety and biological effect, as well as identify the recommended Phase IIa dose.

Phase IIa portion of the study: The Phase IIa study is an open-label, single-dose level study. All participants who are eligible to receive treatment on study will receive the same dose level for both BP1001 (the HTD or 1 level below the HTD) as determined by the Phase Ib study and Das (140 mg). There will be no randomization for this study. The Phase IIa study will compare the efficacy of the BP1001 in combination with Das to historical response rates documented for Das alone, and will evaluate the PK of BP1001, when given alone or in combination with Das.

Approximately 40 evaluable participants will receive the combination of BP1001 with Das in Phase IIa.

Study Design

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Study Type :	Interventional (Clinical Trial)
Estimated Enrollment :	46 participants
Allocation:	Non-Randomized
Intervention Model:	Parallel Assignment
Masking:	None (Open Label)
Primary Purpose:	Treatment
Official Title:	A Phase Ib/IIa Single-arm, Open-label Clinical Trial to Evaluate the Safety, Pharmacokinetics, and Efficacy of BP1001 (a Liposomal Grb2 Antisense Oligonucleotide) in Combination With Dasatinib (Das) in Patients With Philadelphia Chromosome Positive (Ph+) Chronic Myelogenous Leukemia (CML) in Accelerated or Blast Phase
Actual Study Start Date :	September 1, 2017
Estimated Primary Completion Date :	November 2019
Estimated Study Completion Date :	November 2020

Arms and Interventions

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Arm	Intervention/treatment
Experimental: BP1001 (varying dose) + Dasatinib; Phase 1b: BP1001 (varying dose levels) in combination with Das	Drug: BP1001 (varying dose); BP1001 (varying dose); Other Names: Liposomal Grb-2; L-Grb-2; Drug: Dasatinib; Dasatinib; Other Name: Das
Experimental: BP1001 (fixed dose) + Dasatinib; Phase IIa: BP1001 (fixed dose based on Phase 1b) in combination with Das	Drug: BP1001 (fixed dose); BP1001 (fixed dose); Other Names: Liposomal Grb-2; L-Grb-2; Drug: Dasatinib; Dasatinib; Other Name: Das

Outcome Measures

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Primary Outcome Measures :

1. Dose Limiting Toxicity of BP1001 using non-hematologic and hematologic parameters per NCI CTCAE criteria [ Time Frame: 180 days ]
   Phase 1b portion of the study: Determine the dose limiting toxicity of BP1001 in combination with Das
2. Maximum Tolerated Dose of BP1001 using non-hematologic and hematologic parameters per NCI CTCAE criteria [ Time Frame: 180 days ]
   Phase 1b portion of the study: Determine the maximum tolerated dose of BP1001 in combination with Das
3. Efficacy of the combination of BP1001 and Das using hematologic response by bone marrow aspirate or biopsy and complete blood counts [ Time Frame: 180 days ]
   Phase IIa portion of the study: Assess the efficacy of the combination of BP1001 and Das
4. Efficacy of the combination of BP1001 and Das using cytogenetic response (karyotyping) by bone marrow aspirate or biopsy [ Time Frame: 180 days ]
   Phase IIa portion of the study: Assess the efficacy of the combination of BP1001 and Das
5. Efficacy of the combination of BP1001 and Das using molecular response (PCR) by bone marrow aspirate or biopsy [ Time Frame: 180 days ]
   Phase IIa portion of the study: Assess the efficacy of the combination of BP1001 and Das

Secondary Outcome Measures :

1. Safety of BP1001 in combination with Das using non-hematologic and hematologic parameters per NCI CTCAE criteria [ Time Frame: 30 days ]
   Evaluate Safety of BP1001 in combination with Das
2. Efficacy of the combination of BP1001 and Das using hematologic response by bone marrow aspirate or biopsy and complete blood counts versus Das alone by historical outcome comparison [ Time Frame: 180 days ]
   Determine whether the combination of BP1001 and Das provides greater efficacy (Hematologic Response) than Das alone (by historical comparison)
3. Efficacy of the combination of BP1001 and Das using cytogenetic response (karyotyping) by bone marrow aspirate or biopsy versus Das alone by historical outcome comparison [ Time Frame: 180 days ]
   Determine whether the combination of BP1001 and Das provides greater efficacy (Cytogenetic Response) than Das alone (by historical comparison)
4. Efficacy of the combination of BP1001 and Das using molecular response (PCR) by bone marrow aspirate or biopsy versus Das alone by historical outcome comparison [ Time Frame: 180 days ]
   Determine whether the combination of BP1001 and Das provides greater efficacy (Molecular Response) than Das alone (by historical comparison)
5. In vivo PK using plasma to compute half life and elimination [ Time Frame: 30 days ]
   Evaluate in vivo PK of BP1001 when given alone and in combination with Das
6. Time to Response using hematologic response using bone marrow biopsy or aspirate and complete blood counts [ Time Frame: 30 days ]
   Assess time to response from administration of BP1001 + Das to hematologic response
7. Time to Response using cytogenetic response (karyotyping) using bone marrow biopsy or aspirate [ Time Frame: 30 days ]
   Assess time to response from administration of BP1001 + Das to cytogenetic response
8. Time to Response using molecular response (PCR) using bone marrow biopsy or aspirate [ Time Frame: 30 days ]
   Assess time to response from administration of BP1001 + Das to molecular response
9. Duration of Response using hematologic response using bone marrow biopsy or aspirate and complete blood counts from day of response to day of disease progression [ Time Frame: 30 days ]
   Assess duration of response from day of response to day of disease progression
10. Duration of Response using cytogenetic response (karyotyping) using bone marrow biopsy or aspirate from day of response to day of disease progression [ Time Frame: 30 days ]
    Assess duration of response from day of response to day of disease progression
11. Duration of Response using molecular response (PCR) using bone marrow biopsy or aspirate from day of response to day of disease progression [ Time Frame: 30 days ]
    Assess duration of response from day of response to day of disease progression
12. Overall Survival from date of study entry to study closure [ Time Frame: 180 days ]
    Assess overall survival from date of study entry to study closure

Eligibility Criteria

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Ages Eligible for Study:	18 Years and older (Adult, Older Adult)
Sexes Eligible for Study:	All
Accepts Healthy Volunteers:	No

Criteria

Inclusion Criteria:

1. Adults ≥18 years of age
2. Females must be of non-childbearing potential, surgically sterile, postmenopausal, or practice adequate methods of contraception during the study and for 30 days after the last dose of study drug or Das
3. Males must agree to use an adequate method of contraception during the study and for at least 30 days after the last dose of study drug or Das

4. Histologically documented diagnosis of Ph+ CML, in accelerated or blast phase.

   One of the following parameters is required to meet criteria for accelerated CML:

   • Blasts in Peripheral Blood or Bone Marrow ≥15% (either myeloid or lymphoid blasts)
   • Promyelocytes and Blasts in Peripheral Blood or Bone Marrow ≥30%
   • PB or BM basophils ≥20%
   • Thrombocytopenia <100 x 103/ml, not resulting from therapy
   • Cytogenetic clonal evolution Blast phase is defined as ≥30% blasts in peripheral blood or bone marrow, or presence of extramedullary disease, except for liver or spleen.

5. Adequate hepatic and renal functions as defined by:

   1. Aspartate transaminase (AST) and alanine transaminase (ALT) ≤2.5 times the upper limit of normal (ULN); and
   2. Total bilirubin ≤1.5 times ULN; and
   3. Estimated glomerular filtration rate (eGFR) of at least 50 ml/min; the Cockcroft Gault formula will be utilized to determine eGFR when blood urea nitrogen (BUN) and creatinine testing are performed at baseline. The combination of eGFR serum creatinine and BUN will be used to evaluate patient's renal function for safety assurance.
6. Documented Eastern Cooperative Oncology Group (ECOG) performance status of 0, 1, or 2
7. Recovered from the effects of any prior surgery, radiotherapy, or antineoplastic treatment (with the exception of alopecia), based on Investigator assessment
8. Willing and able to provide written informed consent

Exclusion Criteria:

1. Patients with T315I mutation will not be excluded, but their response will be analyzed separately.
2. Another primary malignancy other than CML within the past 2 years except non-melanoma skin cancer, or carcinoma in situ of the cervix.
3. Known, active leptomeningeal leukemia requiring intrathecal therapy. NOTE: Patients with a history of CNS disease may be allowed to participate based on at least 2 consecutive documented, negative spinal fluid assessment prior to Screening
4. Isolated extramedullary leukemia without also meeting bone marrow criteria for leukemia
5. Receipt of any anti-cancer therapy within 14 days of starting BP1001, with the exception of hydroxyurea or anagrelide, or TKI (within 2 days)
6. Uncontrolled active, untreated, or progressive infection
7. Receipt of any investigational agent within 14 days or 5 half-lives of starting BP1001
8. Females who are pregnant, test positive for pregnancy, or are breast-feeding during the Screening period, or intend to become pregnant or breast-feed during the course of the study or within 30 days after last dose of study drug
9. Prior exposure to BP1001
10. Patients with a history of intolerance to Das or for whom Das might not be appropriate
11. Serious intercurrent medical or psychiatric illness which, in the opinion of the Investigator, would interfere with the ability of the participant to complete the study
12. Active/chronic hepatitis B infection (based on positive surface antigen [HBsAg]), hepatitis C infection (based on positive antibody [HCV Ab]), or human immunodeficiency virus (HIV-1 or HIV-2, based on positive antibody)
13. Presence of concurrent conditions that, in the opinion of the Investigator and/or Medical Monitor, may compromise the participant's ability to tolerate study treatment or interfere with any aspect of study conduct or interpretation of results. This includes, but is not limited to, unstable or uncontrolled angina, New York Heart Association (NYHA) class III or IV congestive heart failure, uncontrolled and sustained hypertension, clinically significant cardiac dysrhythmia or clinically significant ECG abnormality (eg, QTcF >470 msec)
14. Within the past 6 months, has had any of the following: pleural effusion, myocardial infarction, unstable angina pectoris, coronary/peripheral artery bypass graft, cerebrovascular accident or transient ischemic attack
15. Uncontrolled seizure disorder (ie, seizures within the past 2 months).
16. Unable or unwilling to communicate or cooperate with the Investigator or follow the protocol for any reason

Contacts and Locations

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Contacts

Contact: Maro Ohanian, M.D.	713-792-2631	mohanian@mdanderson.org
Contact: Yesid Alvarado-Valero, M.D.	713-794-4364	yalvarad@mdanderson.org

Locations

United States, Texas
The University of Texas M.D. Anderson Cancer Center	Recruiting
Houston, Texas, United States, 77030
Contact: Maro Ohanian, M.D. 713-792-2631 mohanian@mdanderson.org

Sponsors and Collaborators

Bio-Path Holdings, Inc.

Investigators

Principal Investigator:	Maro Ohanian, M.D.	M.D. Anderson Cancer Center

More Information

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Responsible Party:	Bio-Path Holdings, Inc.
ClinicalTrials.gov Identifier:	NCT02923986 History of Changes
Other Study ID Numbers:	BP1001-202-CML
First Posted:	October 5, 2016
Last Update Posted:	January 18, 2018
Last Verified:	January 2018
Individual Participant Data (IPD) Sharing Statement:
Plan to Share IPD:	Undecided

Studies a U.S. FDA-regulated Drug Product:		Yes
Studies a U.S. FDA-regulated Device Product:		No

Keywords provided by Bio-Path Holdings, Inc.:

Liposomal Grb-2 treatment of Ph+ CML; Liposomal Grb-2 with Das for Ph+ CML

Additional relevant MeSH terms:

Leukemia; Leukemia, Myeloid; Leukemia, Myelogenous, Chronic, BCR-ABL Positive; Neoplasms by Histologic Type; Neoplasms; Myeloproliferative Disorders; Bone Marrow Diseases	Hematologic Diseases; Dasatinib; Antineoplastic Agents; Protein Kinase Inhibitors; Enzyme Inhibitors; Molecular Mechanisms of Pharmacological Action